The two main protocols for this project have been approved and are in active recruitment and accrual stages now. We continue to enroll a cohort of patients with severe atopic dermatitis (AD) alone, and those with AD in the context of immune deficiency. We have a substantial cohort of patients with genetic disorders, which include atopy as a part of the syndrome (now numbering over 200 patients total). The main findings that have occurred in this project within the past year, describted in detail below. Finding 1: We had previously shown that patients with loss of function mutations in STAT3 appeared to be protected from anaphylaxis and that mast cell degranulation was dependent upon STAT3. We have now further extended that finding by showing that while indeed human mast cells are dependent upon STAT3 for degranulation, mice are not-- yet patients and the mouse model are protected from anaphylaxis. It appears that endothelial cell responsed to histamine which lead to vascular leakage in allergic responses are markedly impaired when STAT3 is inhibited. In vivo histamine-induced anaphylaxis in mice is impaired in the STAT3mut mouse, and endothelial cells derived from patients with HIES are resistant to histamine induced permeability. Furthermore, using a small molecule inhibitor of STAT3 we can recapitulate these findings in normal mice, further showing that STAT3 inhibition can be used to prevent anaphylaxis. These findings, along with further mechanistic work, are under review. Finding 2: Wet-wrap therapy is a mainstay of care for our patients with severe atopic dermatitis regardless of underlying etiology. We have now performed this therapy on over 50 patients refractory to the outpatient standard of care. We have found that while there is a transient drop in morning cortisol levels, this recovers, and there are few short or long term adverse affects of this therapy up to 2 years of follow up. We also found that there is an acute drop in circulating eosinophils, which recovers slightly, but then remains low up to two years of follow up. The long-term improvement in objective rash burden as well as subjective quality of life measures is quite significant (nearly 50% for all) and never before observed for such a prolonged follow up period in such a diverse patient group-- 1-2 years. In addition, we have performed this procedure on a variety of different immune deficiencies, including Chronic Granulomatous Disease, Dock8 deficiency, PGM3 deficiency and STAT3 deficiency. Our use of wet-wraps to improve barrier function as part of the preparation prior to conditioning and transplant in Dock8 patients has been reported (Cuellar-Rodriguez, Biol Blood Marrow Transplant. 2015). Our success in those patients has both demonstrated the safety and the utility of the wraps in those conditions. A manuscript describing the other findings is in preparation